Abnormalities in intracellular regulation in cystic fibrosis

Abnormalities in intracellular regulation in cystic fibrosis (CF) result from a given mutation in the cytoplasmic domain of CFTR, which renders it unable to respond correctly to agonists acting at the cell surface. This results in altered composition of epithelial secretions, which leads to some of the clinical manifestations of CF. Investigation of cyclic AMP- and Ca(2+)-mediated pathways controlling secretion is crucial for understanding how CFTR fails to respond to stimuli and how to reverse the defect in a CF cell. It should be feasible either to upregulate abnormal CFTR activity or to bypass the defect in the cell by stimulating a compensatory signalling pathway. Although their mechanism of action is unknown, one class of compounds, the methylxanthines, have been shown to reverse a fundamental CF abnormality in CF salivary cells and in non-epithelial cells overexpressing CFTR. This affords the exciting possibility that agents acting on intracellular signal transduction pathways will prove to be useful in devising new drug strategies for CF.